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The Effect of Phenobarbital on Cyclophosphamide Antitumor Activity¹

The Section of Hematology-Oncology, Department of Internal Medicine, University of Arizona College of Medicine, Tucson, Arizona 85724 [D. S. A.], and Department of Microbiology, University of California School of Medicine, San Francisco, California 94143 [T. v. D. W.]

We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of microsomal enzyme induction by phenobarbital on the antileukemic activity and bone marrow toxicity of cyclophosphamide. Phenobarbital drinking water (0.5 mg/ml) was given for 7 days prior to cyclophosphamide (10 to 200 mg/kg i.p.). Average daily phenobarbital intake per mouse was 1.25 mg (equivalent to 4 mg/kg/day human dosage). Dose-response curves with and without phenobarbital pretreatment showed a constant 90% (1-log) reduction in the toxicity of cyclophosphamide to leukemic colony-forming units, whereas enzyme induction had no effect on the toxicity of the drug to normal bone marrow colony-forming units. Parallel survival studies confirmed the 1-log diminution in the antileukemic activity of cyclophosphamide in phenobarbital-pretreated mice. This phenobarbital-induced change in the antitumor activity of cyclophosphamide appears explainable on a pharmacokinetic basis. The Friedman and Boger assay for plasma alkylating metabolites showed that the reduction in the area under the plasma metabolite curve caused by enzyme induction exactly predicted the observed reduction in cyclophosphamide antitumor effect.

¹ This investigation was supported in part by Clinical Cancer Research Center Grant CA-11067 (to the University of California) and Medical Oncology Program Project Grant CA-17094 (to the University of Arizona) from the National Cancer Institute, NIH, Bethesda, Md.; the Faculty Training Grant in Clinical Pharmacology from the Pharmaceutical Manufacturing Association, Washington, D. C.; and the Cancer Coordinating Committee Grant from the University of California, Berkeley, Calif. Presented in part at the Annual Meeting of the American Federation of Clinical Research, May 1975 (1).

² To whom requests for reprints should be addressed.

Received 11/ 6/75. Accepted 4/20/76.

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